In vivo Two-Photon Imaging Reveals Acute Cerebral Vascular Spasm and Microthrombosis After Mild Traumatic Brain Injury in Mice

Abstract

Mild traumatic brain injury (mTBI), or concussion, is reported to interfere with cerebral blood flow and microcirculation in patients, but our current understanding is quite limited and the results are often controversial. Here we used longitudinal in vivo twophoton imaging to investigate dynamic changes in cerebral vessels and velocities of red blood cells (RBC) following mTBI. Closed-head mTBI induced using a controlled cortical impact device resulted in a significant reduction of dwell time in a Rotarod test but no significant change in water maze test. Cerebral blood vessels were repeatedly imaged through a thinned skull window at baseline, 0.5, 1, 6 h, and 1 day following mTBI. In both arterioles and capillaries, their diameters and RBC velocities were significantly decreased at 0.5, 1, and 6 h after injury, and recovered in 1 day post-mTBI. In contrast, decreases in the diameter and RBC velocity of venules occurred only in 0.5-1 h after mTBI. We also observed formation and clearance of transient microthrombi in capillaries within 1 h post-mTBI. We concluded that in vivo two-photon imaging is useful for studying earlier alteration of vascular dynamics after mTBI and that mTBI induced reduction of cerebral blood flow, vasospasm, and formation of microthrombi in the acute stage following injury. These changes may contribute to early brain functional deficits of mTBI.

Blood–Brain Barrier Dysfunction in Mild Traumatic Brain Injury: Evidence From Preclinical Murine Models

“…For instance, histological evidence from human patients indicated that microvascular dysfunction widely occurred from mild to moderate and severe TBI, and not only in the acute and subacute stages after the primary injury but also in the chronic stage in long-term survivors ( O’Keeffe et al, 2020 ). These clinical findings are in general backed up by the evidence from preclinical animal models ( Sandsmark et al, 2019 ), which demonstrated that mTBI induces cellular and molecular events at the BBB, including alteration of endothelial transport functions ( Villalba et al, 2017 ), disruption of the crosstalk between endothelial cells and pericytes ( Bhowmick et al, 2019 ), pericyte loss ( Zehendner et al, 2015 ), cerebral blood flow (CBF) reduction, and tissue hypoxia ( Han et al, 2020 ; O’Keeffe et al, 2020 ). These vascular pathological events interact and evolve with neuroinflammation ( Blennow et al, 2012 ) and contribute to chronic neurodegeneration post-injury.…”

Low-level blast exposure induces chronic vascular remodeling, perivascular astrocytic degeneration and vascular-associated neuroinflammation

“…Because gliovascular and neurovascular interactions control cerebral blood flow at multiple levels, their disruption following blast exposure would be expected to affect cerebral autoregulation. Morphological, biochemical and functional studies of humans and animal models have identified the vasculature as a primary target for blast-induced tissue damage [ 2 , 6 , 32 , 38 – 41 , 45 , 50 , 54 , 63 , 66 , 75 , 82 , 112 – 114 , 116 , 130 – 133 , 138 ]. Considerable evidence supports the concept of a thoracic effect whereby pressure waves transmitted through the systemic circulation damage the brain providing an additional mechanism for why blood vessels and perivascular cellular elements may be particularly susceptible to blast injury [ 116 , 117 ].…”

Impaired Glutamate Receptor Function Underlies Early Activity Loss of Ipsilesional Motor Cortex after Closed-Head Mild Traumatic Brain Injury

“…Preparation of mTBI model: mTBI was created using a technique described recently 16,17 . Before injury, mice were anesthetized with a mixture of ketamine (87.7 mg/mL) and xylazine (12.3 mg/mL) and placed in a stereotaxic frame.…”